This is a competing continuation application for renewal (Years #26-#31, 12/1/06-11/30/11) of a K05 Senior Scientist Award held since 8/01/81. To date, the overall objective of the research has been to investigate through epidemiological studies three major themes on drug use in adolescence and adulthood: (1) developmental patterns of involvement and cessation in the use of drugs;(2) risk and protective factors for drugs involvement;and (3) consequences of drug use. Over the past 5 years, I have focused mostly on nicotine dependence and initiated a multifactorial examination of the development of nicotine dependence in a cohort of young adolescents followed over a two-year period. In the next period, my goal is to continue to investigate the development and consequences of nicotine dependence and to implement genetic and animal studies that will expand the research into the new area of molecular drug epidemiology. Nine aims will be pursued: (1) Describe the epidemiology, natural history, and developmental patterns of nicotine dependence among adolescents and young adults. (2) Identify psychological, social and biological factors that promote (risk factors) and factors that reduce the risk (protective factors) of the transition to nicotine dependence. (3) Specify the comorbidity of drug use and dependence with psychiatric symptoms among adolescents, in particular the sequencing and reciprocal relationships between nicotine dependence and depression. (4) Examine familial similarity on dependence between parents and offspring. (5) Identify pathways of progression in smoking, nicotine dependence, and the use of other drugs;(6) Identify candidate genes related to nicotine dependence in adolescence;(7) Identify in the mouse molecular changes in gene expression related to patterns of nicotine exposure modeled on human epidemiological findings. (8) Confirm the causal role of candidate genes for nicotine dependence by inserting or ablating these genes in mice to study their role in patterns of self-administration of nicotine. (9) Identify gender and ethnic commonalities and differences for #1-#7. Three interrelated research programs will be pursued to achieve these aims: (a) Continuation and extension of the longitudinal study of the transition to nicotine dependence in adolescence (TND);(b) Analysis of a forthcoming fourth wave of data in a national longitudinal sample of young adults (Add Health), (c) In collaboration with neurobiologists and a behavioral pharmacologist, identification of molecular mechanisms and associated genes underlying nicotine and cocaine consumption in animal models. The research will provide understanding crucial for the development of effective prevention and treatment interventions. An overall goal is to expand and strengthen a biological perspective in epidemiological research. Components of the program represent innovative activities in the new area of molecular drug epidemiology.